miR-218 Directs a Wnt Signaling Circuit to Promote Differentiation of Osteoblasts and Osteomimicry of Metastatic Cancer Cells

Hassan, Mohammad Q.; Maeda, Yukiko; Taipaleenmäki, Hanna; Zhang, Weibing; Jafferji, Mohammad; Gordon, Jonathan A. R.; Li, Zhaoyong; Croce, Carlo M.; Wijnen, André J. van; Stein, Janet L.; Lian, Jane B.

doi:10.1074/jbc.m112.377515

Cited by 256 publications

(227 citation statements)

References 53 publications

(27 reference statements)

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“…It has been shown that miR-218 expression is downregulated in many tumors including ESCC (15)(16)(17)(18)(19)(20) and is involved in cancer initiation and development (15)(16)(17)(18)(19)(20)(21)(22) SOT (38), Rob1 receptor (39) as well as LAmb3 (40), which are involved in several different signaling pathways, suggesting that miR-218 is a tumor suppressor miRNA and plays a crucial role in the initiation, development and metastasis of tumors. Therefore, we reasonably speculated that miR-218 suppresses the tumor growth of ESCC in vitro and in vivo by regulating multiple target genes.…”

Section: Discussionmentioning

confidence: 99%

miR-218 suppresses tumor growth and enhances the chemosensitivity of esophageal squamous cell carcinoma to cisplatin

et al. 2014

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Abstract.A growing body of evidence suggests that microRNA-218 (miR-218) acts as a tumor suppressor and is involved in tumor progression, development and metastasis and confers sensitivity to certain chemotherapeutic drugs in several types of cancer. However, our knowledge concerning the exact roles played by miR-218 in esophageal squamous cell carcinoma (ESCC) and the underlying molecular mechanisms remain relatively unclear. Thus, the aims of this study were to detect the expression of miR-218 in human ESCC tissues and explore its effects on the biological features and chemosensitivity to cisplatin (CDDP) in an ESCC cell line (Eca109), so as to provide new insights for ESCC treatment. Here, we found increased expression of miR-218 in the ESCC tissues compared with that in the matched non-tumor tissues, and its expression level was correlated with key pathological characteristics including clinical stage, tumor depth and metastasis. We also found that enforced expression of miR-218 significantly decreased cell proliferation, colony formation, migration and invasion, induced cell apoptosis and arrested the cell cycle in the G0/G1 phase, as well as suppressed tumor growth in a nude mouse model. In addition, our results showed that miR-218 mimics increased the sensitivity to the antitumor effect of CDDP in the human Eca109 cells. Importantly, this study also showed that miR-218 regulated the expression of phosphorylated PI3K, AKT and mTOR, which may contribute to suppressed tumor growth of ESCC and enhanced sensitivity of ESCC cells. These findings suggest that miR-218 is a potential therapeutic agent for the treatment of ESCC.

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Section: Discussionmentioning

confidence: 99%

miR-218 suppresses tumor growth and enhances the chemosensitivity of esophageal squamous cell carcinoma to cisplatin

et al. 2014

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“…These effects correlate with a decreased expression of Sfrp2, Sost, and Dkk2. Moreover, BMP and Wnt stimuli induce higher miR-218 levels, leading to the upregulation of b-catenin and Tcf1 (Hnf1a) expression and therefore linking miR-218 to a positive loop mechanism involving Wnt signaling (Hassan et al 2012). Dkk1 is also a miRNA target, leading to enhanced Wnt signaling.…”

Section: The Interplay Between Mirnas and Wnt/b-catenin Signalingmentioning

confidence: 99%

MicroRNAs and post-transcriptional regulation of skeletal development

Gámez¹,

Rodríguez-Carballo²,

Ventura³

2014

Journal of Molecular Endocrinology

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MicroRNAs (miRNAs) have become integral nodes of post-transcriptional control of genes that confer cellular identity and regulate differentiation. Cell-specific signaling and transcriptional regulation in skeletal biology are extremely dynamic processes that are highly reliant on dose-dependent responses. As such, skeletal cell-determining genes are ideal targets for quantitative regulation by miRNAs. So far, large amounts of evidence have revealed a characteristic temporal miRNA signature in skeletal cell differentiation and confirmed the essential roles that numerous miRNAs play in bone development and homeostasis. In addition, microarray expression data have provided evidence for their role in several skeletal pathologies. Mouse models in which their expression is altered have provided evidence of causal links between miRNAs and bone abnormalities. Thus, a detailed understanding of the function of miRNAs and their tight relationship with bone diseases would constitute a powerful tool for early diagnosis and future therapeutic approaches.

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“…MiR-218 stimulates the Wnt pathway in breast cancer cells by directly targeting the Wnt inhibitors SOST, DKK2 and SFRP2 that have the potential to enhance the expression of osteoblastic genes in metastatic cells. 62 This osteomimetic gene expression has the potential to influence metastatic cell homing to the bone. An additional study found that miR-204, miR-211 and miR-379 regulate interleukin (IL)-11 expression in breast cancer cells.…”

Section: Tumor-intrinsic Mirna Regulation Of Bone Metastasismentioning

confidence: 99%

MicroRNAs as regulators of bone homeostasis and bone metastasis

Ell

Kang

2014

Bonekey Reports

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MicroRNAs (miRNAs) are short, endogenous RNAs that have essential roles in regulating gene expression through the disruption of target genes. The miRNA-induced suppression can occur through Argonaute-mediated cleavage of target mRNAs or by translational inhibition. System-wide studies have underscored the integral role that miRNAs play in regulating the expression of essential genes within bone marrow stromal cells. The miRNA expression has been shown to enhance or inhibit cell differentiation and activity, and elucidating miRNA targets within bone marrow cells has revealed novel regulations during normal bone development. Importantly, multiple studies have shown that miRNA misexpression mediates the progression of bone-related pathologies, including osteopetrosis and osteoporosis, as well as the development and progression of osteosarcoma. Furthermore, recent studies have detailed the capacity for miRNAs to influence bone metastasis from a number of primary carcinomas. Taken together, these findings reveal the significant clinical potential for miRNAs to regulate bone homeostasis, as well as to mediate bone-related pathologies.BoneKEy Reports 3, Article number: 549 (2014) | doi:10.1038/bonekey.2014.44 MiRNA Biogenesis and FunctionThe past decade has seen a torrent of novel research into the post-translational regulation of genes via microRNA-mediated suppression. The microRNAs (miRNAs) are a class of B22-nucleotide-long RNAs that repress gene expression through complementary binding to sites in the 3 0 -untranslated region (UTR) of target mRNAs. 1 Mature miRNAs are generated by the sequential cleavage of longer precursor transcripts, or pri-miRNAs, that are typically transcribed from intragenic or intergenic regions by RNA polymerase II. 2 The initial cleavage step, mediated by Drosha and the DGCR8 complex, occurs in the nucleus and produces a shortened (70-100 nucleotides) pre-miRNA hairpin. Pre-miRNAs are exported from the nucleus by Exportin 5, followed by a second cleavage by the ribonuclease Dicer that produces a double-stranded, B18-25-nucleotide-long mature miRNA. One miRNA strand will then combine with Argonaute (AGO2) proteins to produce an RNAinduced silencing complex, allowing for directed pairing with target mRNAs. 1

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miR-218 Directs a Wnt Signaling Circuit to Promote Differentiation of Osteoblasts and Osteomimicry of Metastatic Cancer Cells

Cited by 256 publications

References 53 publications

miR-218 suppresses tumor growth and enhances the chemosensitivity of esophageal squamous cell carcinoma to cisplatin

miR-218 suppresses tumor growth and enhances the chemosensitivity of esophageal squamous cell carcinoma to cisplatin

MicroRNAs and post-transcriptional regulation of skeletal development

MicroRNAs as regulators of bone homeostasis and bone metastasis

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